Atrial fibrillation (AF) and atrial flutter are the most common cardiac arrhythmias in clinical practice and are likely to increase in prevalence with the aging of the population. Currently, AF affects more than 1 million Americans annually, represents over 5% of all admissions for cardiovascular diseases, and causes more than 80,000 strokes each year in the United States. While AF is rarely a lethal arrhythmia, it is responsible for substantial morbidity and can lead to complications such as the development of congestive heart failure or thromboembolism. Currently available Class I and Class III antiarrhythmic drugs reduce the rate of recurrence of AF, but are of limited use because of a variety of potentially adverse effects including ventricular proarrhythmia. Because current therapy is inadequate and fraught with side effects, there is a clear need to develop new therapeutic approaches.
Antiarrhythmic agents of Class III are drugs that cause a selective prolongation of the duration of the action potential without significant cardiac depression. Available drugs in this class are limited in number. Examples such as sotalol and amiodarone have been shown to possess interesting Class III properties (Singh B. N., Vaughan Williams E. M. “A Third Class of Anti-Arrhythmic Action: Effects On Atrial And Ventricular Intracellular Potentials And Other Pharmacological Actions On Cardiac Muscle, of MJ 1999 and AH 3747” Br. J. Pharmacol 1970; 39: 675-689. and Singh B. N., Vaughan Williams E. M, “The Effect of Amiodarone, A New Anti-Anginal Drug, On Cardiac Muscle”, Br J. Pharmacol 1970; 39: 657-667), but these are not selective Class III agents. Sotalol also possesses Class II effects which may cause cardiac depression and is contraindicated in certain susceptible patients. Amiodarone also is not a selective Class III antiarrhythmic agent because it possesses multiple electrophysiological actions and is severely limited by side effects (Nademanee, K. “The Amiodarone Odessey”. J. Am. Coll. Cardiol. 1992; 20:1063-1065.) Drugs of this class are expected to be effective in preventing ventricular fibrillation. Selective class III agents, by definition, are not considered to cause myocardial depression or an induction of arrhythmias due to inhibition of conduction of the action potential as seen with Class I antiarrhythmic agents.
Class III agents increase myocardial refractoriness via a prolongation of cardiac action potential duration. Theoretically, prolongation of the cardiac action potential can be achieved by enhancing inward currents (i.e. Na+ or Ca2+ currents; hereinafter INa and ICa, respectively) or by reducing outward repolarizing potassium (K+) currents. The delayed rectifier (IK) K+ current is the main outward current involved in the overall repolarization process during the action potential plateau, whereas the transient outward (Ito) and inward rectifier (IKI) K+ currents are responsible for the rapid initial and terminal phases of repolarization, respectively. Cellular electrophysiologic studies have demonstrated that IK consists of three pharmacologically and kinetically distinct K+ current subtypes, IKu (rapidly activating and deactivating) and IKs (slowly activating and deactivating) (Sanguinetti and Jurkiewicz, Two Components Of Cardiac Delayed Rectifier K+ Current: Differential Sensitivity To Block By Class III Antiarrhythmic Agents, J Gen Physiol 1990, 96:195-215). In addition, the ultra-rapidly activating K+ IKur current is believed to represent the native counterpart to a cloned potassium channel, designated as Kv1.5. While present in the human atrium, it appears to be absent from the human ventricle. Because it is rapidly activating and because of the correspondingly limited slow inactivation, IKur is believed to contribute significantly to repolarization in the human atrium. Consequently, an agent that specifically blocks IKur would prolong refractoriness and retard repolarization of the human atrium in the event of a cardiac arrhythmia, yet at the same time not cause delays in ventricular repolarization. As a result, arrythymogenic after-depolarizations, and acquired long QT syndrome that is observed during treatment with conventional class III antiarrhythmic agents could also be avoided. The effect of IKur in retarding repolarization of the human atrium would also be preventive to the occurrence of atrial fibrillations and arrhythmias.
In intact human atrial myocytes an ultra-rapidly activating delayed rectifier K+ Current IKur which is also known as the sustained outward current, Isus or Iso, has been identified and this current has properties and kinetics identical to those expressed by the human K+ channel clone (hKv1.5, HK2) when isolated from human heart and stably expressed in human (HEK-293) cell lines. (Wang et al., 1993, Circ Res 73: 1061-1076; Fedida et al., 1993, Circ Res 73: 210-216; Snyders et al., 1993, J Gen Physioi 101: 513-543) and originally cloned from rat brain (Swanson et al., 10, Neuron 4: 929-939). Although various antiarrythmic agents are now available on the market, those having both satisfactory efficacy and a high margin of safety have not been obtained. For example, antiarrythmic agents of Class I according to the classification scheme of Vaughan-Williams (“Classification Of Antiarrhythmic Drugs: In: Cardiac Arrhythmias, edited by: E. Sandoe, E. Flensted-Jensen, K. Olesen; Sweden, Astra, Sodertalje, pp 449-472, 1981) which cause a selective inhibition of the maximum velocity of the upstroke of the action potential (Vmax) are inadequate for preventing ventricular fibrillation. In addition, they have problems regarding safety, namely, they cause a depression of myocardial contractility and have a tendency to induce arrhythmias due to an inhibition of impulse conduction. Beta-adrenoceptor blockers and calcium antagonists which belong to Class II and IV, respectively, have a defect in that their effects are either limited to a certain type of arrhythmia or are contraindicated because of their cardiac depressant properties in certain patients with cardiovascular disease. Their safety, however, is higher than that of the antiarrhythmic agents of Class I.
Immunoregulatory abnormalities have been shown to exist in a wide variety of autoimmune and chronic inflammatory diseases, including systemic lupus erythematosis, chronic rheumatoid arthritis, type I and II diabetes mellitus, inflammatory bowel disease, biliary cirrhosis, uveitis, multiple sclerosis and other disorders such as Crohn's disease, ulcerative colitis, bullous pemphigoid, sarcoidosis, psoriasis, ichthyosis, Graves ophthalmopathy and asthma. Although the underlying pathogenesis of each of these conditions may be quite different, they have in common the appearance of a variety of auto-antibodies and self-reactive lymphocytes. Such self-reactivity may be due, in part, to a loss of the homeostatic controls under which the normal immune system operates. Similarly, following a bone-marrow or an organ transplantation, the host lymphocytes recognize the foreign tissue antigens and begin to produce antibodies which lead to graft vs. host rejection.
One end result of an autoimmune or a rejection process is tissue destruction caused by inflammatory cells and the mediators they release. Anti-inflammatory agents such as NSAID's act principally by blocking the effect or secretion of these mediators but do nothing to modify the immunologic basis of the disease. On the other hand, cytotoxic agents, such as cyclophosphamide, act in such a nonspecific fashion in which both the normal and autoimmune responses are shut off. Indeed, patients treated with such nonspecific immunosuppressive agents are as likely to succumb to infection as they are to their autoimmune disease.
Cyclosporin A, which was approved by the US FDA in 1983 is currently the leading drug used to prevent rejection of transplanted organs. In 1993, FK-506 (Prograf) was approved by the US FDA for the prevention of rejection in liver transplantation. Cyclosporin A and FK-506 act by inhibiting the body's immune system from mobilizing its vast arsenal of natural protecting agents to reject the transplant's foreign protein. In 1994, Cyclosporin A was approved by the US FDA for the treatment of severe psoriasis and has been approved by European regulatory agencies for the treatment of atopic dermatitis. Though these agents are effective in fighting transplant rejection, Cyclosporin A and FK-506 are known to cause several undesirable side effects including nephrotoxicity, neurotoxicity, and gastrointestinal discomfort. Therefore, a selective immunosuppressant without these side effects still remains to be developed. Potassium channel inhibitors as described here promise to be the solution to this problem, since inhibitors of Kv1.3, for example, are immunosuppressive. See, Wulff et al., “Potassium channels as therapeutic targets for autoimmune disorders,” Curr Opin Drug Discov Devel. 2003 September; 6(5):640-7; Shah et al., “Immunosuppressive effects of a Kv1.3 inhibitor,” Cell Immunol. 2003 February; 221(2):100-6; Hanson et al., “UK-78,282, a novel piperidine compound that potently blocks the Kv1.3 voltage-gated potassium channel and inhibits human T cell activation,” Br J Pharmacol. 1999 April; 126(8):1707-16.
Inhibitiors of Kv1.5 and other Kv1.x channels stimulate gastrointestinal motility. Thus, the compounds of the invention are believed to be useful in treating motility disorders such as reflux esophagitis. See, Frey et al., “Blocking of cloned and native delayed rectifier K channels from visceral smooth muscles by phencyclidine,” Neurogastroenterol Motil. 2000 December; 12(6): 509-16; Hatton et al., “Functional and molecular expression of a voltage-dependent K(+) channel (Kv1.1) in interstitial cells of Cajal,” J. Physiol. 2001 Jun. 1; 533 (Pt 2): 315-27; Vianna-Jorge et al., “Shaker-type Kv1 channel blockers increase the peristaltic activity of guinea-pig ileum by stimulating acetylcholine and tachykinins release by the enteric nervous system,” Br J Pharmacol. 2003 January; 138(1): 57-62; Koh et al., “Contribution of delayed rectifier potassium currents to the electrical activity of murine colonic smooth muscle,” J. Physiol. 1999 Mar. 1; 515 (Pt 2):475-87.
Inhibitors of Kv1.5 relax pulmonary artery smooth muscle. Thus, the compounds of the invention are believed to be useful in treating hypertension and otherwise improving vascular health. See, Davies et al., “Kv channel subunit expression in rat pulmonary arteries,” Lung. 2001; 179(3): 147-61. Epub 2002 Feb. 04; Pozeg et al., “In vivo gene transfer of the O2-sensitive potassium channel Kv1.5 reduces pulmonary hypertension and restores hypoxic pulmonary vasoconstriction in chronically hypoxic rats,” Circulation. 2003 Apr. 22; 107(15):2037-44. Epub 2003 Apr. 14.
Inhibitors of Kv1.3 increase insulin sensitivity. Hence, the compounds of the invention are believed to be useful in treating diabetes. See, Xu et al., “The voltage-gated potassium channel Kv1.3 regulates peripheral insulin sensitivity,” Proc Natl Acad Sci USA. 2004 Mar. 2; 101 (9): 3112-7. Epub 2004 Feb. 23 (epublished 2004 Feb. 23); MacDonald et al., “Members of the Kv1 and Kv2 voltage-dependent K(+) channel families regulate insulin secretion,” Mol Endocrinol. 2001 Aug.; 15(8): 1423-35; MacDonald et al., “Voltage-dependent K(+) channels in pancreatic beta cells: role, regulation and potential as therapeutic targets,” Diabetologia. 2003 August; 46(8):1046-62. Epub 2003 Jun. 27.
Stimulation of Kv1.1 is believed to reduce seizure activity by hyperpolarizing neurons. Thus, the compounds of the invention are believed to be useful in treating seizures, including seizures associated with epilepsy and other neurological diseases. See, Rho et al., “Developmental seizure susceptibility of kv1.1 potassium channel knockout mice,” Dev Neurosci. 1999 Nov.; 21(3-5): 320-7; Coleman et al., “Subunit composition of Kv1 channels in human CNS,” J. Neurochem. 1999 August; 73(2): 849-58; Lopantsev et al., “Hyperexcitability of CA3 pyramidal cells in mice lacking the potassium channel subunit Kv1.1,” Epilepsia. 2003 December; 44(12): 1506-12; Wickenden, “Potassium channels as anti-epileptic drug targets,” Neuropharmacology. 2002 December; 43(7):1055-60.
Inhibition of Kv1.x channels improves cognition in animal models. Thus, the compounds of the invention are believed to be useful in improving cognition and/or treating cognitive disorders. See, Cochran et al., “Regionally selective alterations in local cerebral glucose utilization evoked by charybdotoxin, a blocker of central voltage-activated K+-channels,” Eur J Neurosci. 2001 November; 14(9): 1455-63; Kourrich et al., “Kaliotoxin, a Kv1.1 and Kv1.3 channel blocker, improves associative learning in rats,” Behav Brain Res. 2001 Apr. 8; 120(1): 35-46.
Based on the foregoing discussion, there is evident in the art a recognized need for pharmaceutical substances belonging to the Kv1.5 subfamily of potassium channel inhibitors that may be used as therapeutic agents, particularly atrial selective thereapeutic agents, in the prevention and treatment of cardiac arrhythymias. Such compounds by virtue of the observed link between Kv1.5 function and other indications as discussed above, would also prove to be useful in a wide range of therapeutic treatment applications associated with Kv1.3 immunoregulatory function. In addition, blockers and activators of Kv1.x channels could be expected to have the utilities described above.